Disubstituted acetamidyl derivatives of amino quinolines



Patented Dec. 21, 1948 UNITED ifi'l'AElii 2,456,911 nrsnns'rrrnreoacr'reiurnrr. nnarva- TIVES F AMZNQ QUKNU LINES No Drawing, ApplicationMay 4, 1945, Serial No. 592,062

7 Claims.

This invention relates in general to the synthesis of a novel group oforganic chemical compounds of the quinoline series, having valuabletherapeutic properties and in particular, relates to the synthesis ofthe quinoline compounds in which the di-N substituted acetamidyl group(-Cl-I2CONRR) is attached through an amino group or bridge to a carbonatom of an alkoXy substituted quinoline ring. structurally, thesequinoline compounds can be represented by the formula QNHCHzCON'RR'wherein Q is an alkoXy substituted quinoline ring and R and R aresimilar or dissimilar hydrocarbon radicals such as alkyl, aryl, aralkylor cycloalkyl groups, for instance, methyl, ethyl, propyl, butyl,phenyl, benzyl, cyclopentyl, and.cyclohexyl radicals or -NRR togetherconstitutes a substituted or unsubstituted heterocyclic ring. Thecompounds of the invention are particularly useful as spasmolytic andlocal anesthetic agents.

The preferred embodiment of my invention is directed to the synthesis ofthe more specific group of compounds represented by the generic formulawherein R, R

alkyl, aryl, aralkyl, or cycioalkyl radicals or wherein NRR' is asubstituted or unsubstituted heterocyclic ring such as piperidyl.

In general, the compounds of the invention may be synthesized byreacting the appropriate N,N-

EXAMPLE I Preparation of N,N-diethyZ-alpha- (fi-methory quinoZinyZ-8)-aminoacetamide 250 grams i diethylamine (360 cc.) were dissolved in3000 cc. of ether and 180 grams (130 cc.) of chloracetyl chloridecontained in 500 cc. of ether were slowly added from a dropping funnel.During the addition, the ether solution of the diethylamine was kept inan ice bath maintained at a temperature of 10 to C. Upon compleand R,"are similar or dissimilar 5 tilled off. Piperidine tion of the reaction,the precipitate of diethylamine hydrochloride was filtered off, theether was evaporated and the residual oil was distilled at 148 to 150 C.under a vacuum of 55 mm. The

yield of N,N-diethyl-alpha-chloracetamide was 246 grams.

grams of 6-methoXy-8-aminoquinoline and 20 cc. ofN,N-diethyl-alpha-chloracetamide were dissolved in 400 cc. of butylalcohol to which was added cc. of piperidine as an acid acceptor. Afterrefluxing for twenty hours, the alcohol was vacuum evaporated off and3000 cc. of diethyl ether added to the residue. The large precipitate ofpiperidine hydrochloride, thus obtained, was filtered off. The etherealfiltrate was distilled on a water bath to remove the ether and theresidue was distilled at 175 to 180 C. under vacuum of 48 to yield 40grams of the desired N,N- diethyl-alpha- (6-methoXy-quinolinyl-8)-aminoacetainide.

AnaZg/sis.-Calcu1ated for C1sI-I21N3O2: 67.0% C, 7.32% H; found: 66.8%C, 7.64% H.

EXAMPLE II Preparation of N,N-dii sopropyl -alpha-(6-methory-qm'noZinyZ-w aminoacetamide grams cc.) of diisopropylaminewere dissolved in ether and a solution of 60 grams (l0 cc.) ofchloracetyl chloride in 500 cc. of ether were added dropwise theretowhile cooling the reaction mixture in an ice bath at 10 to 20" C. Uponcompletion of the reaction, the isopropylamine hydrochloride wasfiltered off, the ether evaporated from the ethereal filtrate and theresidual oil distilled at 162 to 164 C. under a vacuum of 55 mm. Theyield of N,N-diisopropylalpha-chloracetamide was 80 grams.

Analysis-Calculated for CBHlBNOClI 54.05% C, 9.03% H; found: 5 1.11% C,9.31% H. l

so grams of 6-methoXy-8-aminoquinoline and 30 grams of N,l\l-diisopropylchloracetamide were dissolved in 400 cc. of butyl alcohol to which 50cc.

of 'piperidine had been added. After refluxing alcohol was vacuumdishydrochloride was filtered on? after being precipitated by theaddition of 3000 cc. of ether to the residue remaining after the vacuumdistillation. After removal of the other by evaporation on a steam bath,an oil was obtained which'distilled at 178 to 180 C. under a vacuum of45 mm. The yield of N,N-diisopropylealpha- (6 methoxy-quinolinyl-m-aminoacetamide amounted to 50 grams.

AnaZrsis.-Calculated for C sl'lasNsozr C, 7.95% H; found: 68.21%C,'8.14=% H.

for twenty hours, the

EXAMPLE III Preparation of N,Ndz'-npropylalpha- (6-methory-quinoZinyZ-l?) -aminoacetamz'de chloracetyl chloride in 500cc.of ether was "added dropwise thereto with stirring while the reactionflask was kept in an ice bath 10 to C. The precipitate ofdi-n-propylamine hydrochloride formed during the reaction was filtered01f and the ether evaporated. The oily N,N

di n propyl alpha-chloracetamide, remaining after evaporation of theether; distilled at 15211701 154 C. under a vacuum of 55 mm. andamountecl to 71 grams.

AnaZysz's.-Calculated for CsHisNOCl: 54.05%! C, 9.03% H; found: 54.19%C, 9.48% H.

grams of 6-methoxy-S-aminoquinoline and 30 grams ofN,N-di-n-propyl-alpha-chloracetamide were dissolved in 400 cc. ofa'butylalcohol and refiuxedxwith cc; of piperidine for twenty hours. Thealcohol was removed by vacuum; distillation and the residue was treatedwith.3000 cc. ofiether."

to precipitate out piperidinehydrochloride After" filtering off thepiperidine hydrochloride; the ether wasevaporated from the resultingfiltrate to obtainanoil which distilled at 195 C. under a-vacuumof 48-mm; The'yield of N,N-di-npropyl-alpha-(6-methoxy-quinolinyl-8)aminoacetamide'amounted to 52 grams.

Analysis.Calculated for' CiaHzsNsOzi 68.55% C, 7.95%: H; found: 68.47%C, 8.23%H.

EXAMPLE IV Preparation of 'N,N'- dizsobutyl alpha- 6-m'ethoxy-quz'nolinyZ-i) -a.mi1wacetamz'de 250' cc. (190 grams)ofdiisobutylamine were dissolvedin 3000 cc. of ether containedin a flaskwhich was immersed in an ice bath maintained at a temperature'of10'to1'20 'C.. and a solution of. cc. (84 grams) ofchloracetyl chloride"in 500 cc. of ether were added dropwise thereto. The diisobutylaminehydrochloride .formed duringthe reaction wasfiltered' 01f an'd'the'etherevaporated from the filtrate. The oilyN,N-diisob'utyl-alphachloracetamide thus obtained was'distilledat 166to" 168 C. underf avacuum: of 58 mm; and amounted to 160 grams.

AnaZyszs.-Calculated for CioHz0NOC1'2.' 58.4% C, 9 .75% H;found.:'58.l3% C, 10.01%v H.

30 grams of 6-methoxy-8-aminoquinoline,1 35.2

grams. (32 co.) of N,N-diisobutyl-alphawh'loride was obtained. Thepiperidine. hydrochloride acetamide which was: an oil boilingat 200 to205 C. underava'cuum 01547v mm. The yield 'of'prod- 5 not amounted to 48grams.

Amman-Calculated for CzoHzsNaOz: C, 8.46%:1-1; found: 69.72% C, 8.81% H;

2500. of di-n-butylamine were dissolvedin 3000 cc. of ether contained ina reaction flasklime mersed' in an'ice. bath keptiat a temperatureiof ata temperature of 10 to 20 C. and 60 cc. (84 grams) of chloracetylchloride in 500 cc. of ether were added dropwise Upon completion of thereaction, the ether insoluble di-n-butylamine hydrochloride was filteredoff, the ether removed from the filtrate, and the residual oildistilledat 180 to 182.

' C. under a vacuum of 55 mm. The yield of N,N-

di-n-butyl-alpha-chloracetamide thus obtained was grams.

AnaZysis.-Calculated for CmHzoNOCl: C, 9:75.% H'; found: 58.31% C, 9.94%H.

30 grams of '6-methoxy-8-aminoquinoline, 35.2 grams (32- cc.) ofN-,N-di-n-butyl-alpha-chloracetamide and 50 cc. of piperidine weredissolved in400cc. of butyl alcohol and. refluxed for twenty hours. Thealcohol was vacuum evaporated and 3000 cc. of diethyl ether were addedto the residue. The large precipitate of piperidine hydrochloride, thusobtained, was filtered off and the ether distilled 01? from thefiltrate. The oily residuewhich remained. was distilled at 212 .to2l4"C. under a vacuum of 47 mm. The yield of N,N- di-n-butyl-alpha-(G-methoxy-quinolinyl-S) -aminoacetamideamounted to 51 grams.

Analysis.eCalculated for C20H29N3O2Z 8.46%.H; found: 69.84% C, 8.63% H.

v EXAMPLE VI Preparation of N,N-di-n-amyl-alpha-(G-methoxy-quz'nolinyl-?) -a.minoacetamide 45' grams of di-n-amylaminewere dissolved in 2000' cc. of ether cc.) of chloracetyl chloride- Wereadded dropwise:

Man icebath. Upon completion of the reaction, the precipitateof'di-n-amylamine hydrochloride'was filtered ofi, the from the filtrate,and the residual oil distilled at 198 to 200 C. undera vacuum of 58 mm.Thesolidified to a solid.

Analysis-Calculated for C22H33N3O2: C, 890% H; found: 73.58% C, 8.88% H.

EXAMPLE VII Preparation of alpha-(6-methoasy-quinolinyl-8)aminoacetylpz'peridide 200 grams of piperidine (230700;) WGIedl'SSOIVEd.in 3000 cc. of diethyl ether and a solution of 88 grams ofN-alpha-chloracetyl. piperidine: and .50..

cc. oifpiperidinewere dissolved in400cc. oibutyl and a solution of 19grams (13 in 250 cc. of ether The temperature of the 'reactionwasmaintained at 10 to 20 C. by means ether evaporated The removal ofpiperidine hydrochloride,

of the product was accomplished, described. in. the above.

aaaema alcohol and refluxed -for-twenty hours. The alcohol was vacuumevaporated off and 3000 cc. of diethyl ether added to the residue to-prec'ipitate out .piperidine hydrochloride. The p'iperidine hydrochloride was filtered off and the ethereal illtra'te wasfirst-'distilledon-a water bath to remove the ether and then wasdistilled-at 193 to 197 C. under a Vacuum of-M mm. onan -oil bath toobtain 48 grams of alpha-KG-methoxy-quinolinyl- 8) -.aminoace'tylpiperidide which is an oil.

Analysis.Calculated for -Cl7H21N3Q2Z 68.25% C, 7.03% H; found: 68.03% C,7.40% H.

By procedures analogous to those described in the above examples, theappropriate aminoquinoline and the appropriateN,N-dialkyl-alphachloracetamide can be reacted to form the followingsubstituted quinolines representative of those comprehended in thisinvention.

e N N-di-n-propyl-alpha-(4-m0thoxy quinolinyLS)-aminoacetam- 6 N 1;-diisobuty1-alpl1a-(4-methoxy quinolinyl-8)-an1inoacctameN,N-di-n-amyl-alpha-(4-methoxy quinolinyl-S) -aminoacetamido NN-(l1-11-propyl-alpha-(itmethoxy quinolinyl-S)-aminoacetamide NlgI-diisobutyl-alpha-(3-methoxy quinolinyl-ti)-aminoaeetam-N,N-diisobutyl-alpha-(B-ethoxy q11i11olinyl-8)aminoacetamideN,N-dhn-amyl-alpha-(3-methoxy quinolinyl-S) aminoacetamide NN-di1s0propyl-alpha-(2-methoxy quinolinyl-S)-aminoacetam- 1de N15T-di-n-pr0py1-alpha-(2-methoxy quinolinyl-S) -aminoacetan1-N,N-diisobutyl-alpha-(Z-ethoxy quinolinyl-8)-aminoacetamide 2) N,N-din-amyl-alpha-(Z-methoxy quinolinyl-8)-aminoacetamide NN-(lhsopropyl-alpha-(7-1nethoxy quinolinyl-S)-am1110acetam- N181-di-n-propyl-alpha(7-methoxy quinolinyl-8)-aminoacetam- N,1(;l-diisobutyl-alpha-(7-methoxy quinolinyl-8)-aminoacetameN,N-di-n-amyl-alpha-(7-methoxy quinolinyl-8)-aminoacetamideN.N-diisopropyl-alpha-(6-propoxy quinolinyl-S)-an1inoacetamide NN-diisobutlyl-alpha-(G-propoxy quinolinyl-S)-aminoaceta1n-N,N-(liisopropyl-alpha-(G-butoxy quino1inyl-8)-a1ninoacetamideN,N-diisobutyl-alpha-(6-butoxy quinolinyl-S)-aminoacetamidcN,N-di-n-amlylalpha-(S-butoxy quinolinyl-8)-aminoacetamide NN-diisopropyl-alpha-((i-methoxy quinolinyl-7)-aminoacetam- Ni-rliisopropyl-alpha-(fi-methoxy quinoliny1-5)-aminoacetam- Nthldiisopropyl-alpha(fi-lnethoxy quinolinyll)-aminoacetam- N N-diisopropyl-alpha-(G-methoxy quinolinyl-3)-aminoaceta1n- Nidiisopropyl-alpha-(Gqnethoxy quinolinyl-2)-aminoacetan1-Niidiisopropyl-alpha-(S-methoxy quino1inyl-8)aminoacetam- N,N-dicyclohexyl-alpha-(S-ethcxy quinlinyl-8)-amin0acetamideN,N-dgcyclopentyl-alpha-(G-mcthoxy quinolinyl-6)-amin0acctarm e Alpha-(i-methoxy quinolinyl-S)-amin0acetyl piperidide A1pha-(3'meth0Xyquinolinyl-8)-amin0acetyl piperidide Alpha-(Z-methoxyquinolinyl-El)-aniinc acetyl pipcrididc A1pha-(7-ethoxyquino1inyl-8)-aminoacetyl piperldide Alpha-(G-butoxyquinoliny1-8)-aminoacetyl piperidide Alpha-(dethoxyquino1inyl-7)-aminoacety1 piperididc Alpha-(G-ethoxyquinolinyl-)-aminoacetyl piperidide Alpha-(G-ethoxy quinoliny1-3)-a1ninoacetyl piperidide Alpha-(G-ethoxy quinolinyl-2) -aminoacety1piperidide Alpha-(-ethoxy quinolinyl-fi)-aminoacctyl piperidide 4N,N-ethyl-propyl-alpha-(G-methoxy quin0linyl-8)-am1noacetamide (61)N,N-ethyl-n-butyl-alpha-(G-methoxy quinolinyl-8)-aminoacetam e (62)N,N-n-propyl-n-butyl-alpha-(G-methcxy quinolinyl-8)-aminoacetamide (63)N;N ethyl-isopr0pyl alpha (6-metl1oxyquinolinyl=8) aminoacetam1 e (64)'N,N ethyl-isobutyhalpha (Gnnethoxy quin0linyl-8)-aminoacetam e (65)N,N-is0pr)pyl-is0buty1-a1pha-(fi-methoxy quino1inyl-8)-aminoac. arm e(66) N,N-ethyl-n-amyl-alpha-(G-methoxy quinolinyl-8)-aminoacetam e (67)N Nethyl al1yl-alpha=(6-methoxy 'quinolinyl-8)-ami11oacetamc (68)N,lgI-cthyl-vinyl-alpha-(fi-methoxy quinolinyl-8)-aminoacetam- 1 e (69)N,N-ethyl-cyclopentyl-alpha-(G-methoxy quinolinyl-8)-aminoac am e (70,).N'N-cthyl propyl-alpha-(B-ethoxy quinolinyl-8)-aminoacetamc (71)N,lgl-ethyl-n-butyl-alpha-(G-ethoxy quinolinyl-8)-amin0acetam- 1 e (72)N,N-ethyl-n-propyl-n-butyl-alpha-(fi-ethoxy quinolinyl-8)-aminoacetamideI (73) N,N-ethyl-isopropyl-alpha-(fi-ethoxy qumol1nyl-8)-ammoacetam e(74) N N-ethyl-isobutyl-alpha-(fi-ethoxy quin0linyl-8)-aminoacetame (75)N,N-isopropyl-isobutyl-alpha-(fi-ethoxy quin0linyl-8)-aminoacam e (76) NlgI-ethyl-n-amyl-alpha-(ii-ethoxy quinolinyl-S)-aminoacetam- 1 e (77)N,N-ethyl-allyl-alpha-(fi-ethoxy quinolinyl-8)-aminoacetamide (7N,N-ethyl-vinyl-alpha-(G-ethoxy quinolinyl-S)-am1noacetam1de (79)N,N-ethyl-cyclopentyl-alpha-(G-ethoxy qulnolinyl-8)-ammoaeetamide Manymodifications of my invention will be apparent to those skilled in theart without departure therefrom or from the scope of the claims, andsince the foregoing disclosure has been given by way of example forclearness and understanding only, no unnecessary limitations should beunderstood and the appended claims should be construed as broadly as thestate of the art permits.

I claim: 1. Substituted alkoxyquinolines of the general formula /R-:--N11cH,co N

where the R"O radical may be substituted in any of the 2-? positions andthe sitions in the quinoline ring and where is a lower alkyl radical andRI is a radical selected from the group consisting of a piperidylradical and a radical where R represents a member of the groupconsisting of alkyl and cycloalkyl radicals and R represents a member ofthe group consisting of alkyl, alkenyl and cycloalkyl radicals.

2. Substituted alkoxy quinolines, according to claim 1, wherein R. is alower alkyl group and R. and R are alkyl radicals.

3. N,N-di-n-butyl alpha-(6 methoxy quinolinyl-8) -aminoacetamide.

4. Substituted alkoxy quinolines, according to claim 1, wherein R" is alower alkyl radical and R and R cycloalkyl radicals.

5. N,N di cyclopentyl alpha quinolinyl-fl) -aminoacetamide.

6. Substituted alkoxy quinolines according to claim 1, wherein R" is alower alkyl radical and (6 methoxy constitutes a piperidyl radical.

7 8 pezidlikgha-(fi-methoxy .quino1iny1-8)-acetyl pi- OTHER REFERENCES II i WILLIAM F. BRUCE. Shriner et 211., Synthetic Antimalarials (Reviewpublished at Bloomington, Ind. 1941) page REFERENCES CITED 5 11. I

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June, 1911), pp, 31, 82, as, 141, and 143. FOREIGN PATENTS ChemicalAbstracts, Vol. 36 (1942), page 5176 Number Country Date 10 [CitingGaind et. al., J. Indian Chem. 800., Vol;

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